This paper describes an animal (rat) model for the study of Bipolar Disorder (BD) in
humans. The paper presents research, previously unpublished, conducted over more than 25 years.
The model is derived from a natural genetic variant discovered in the rat population; these rats
having been all brothers and sisters (littermates) from a single litter that was observed to be hyperactive
in the home cage. The original animals were first inbred and then the offsprings were
selectively-bred for more than 50 generations; this line of rats that proved to be a model for BD was
named the Hyperactive (HYPER) rat.
Findings presented here indicate that this rat model shows similarity to human BD with respect
to the four criteria used to judge/validate any animal model of a human psychological/
psychiatric disorder: (1) etiology, (2) symptomatology, (3) underlying pathophysiology, and (4)
responsiveness to treatments that are effective for the human disorder. To summarize, HYPER rats
mimic manic behavior by showing an outburst of extreme hyperactivity that lasts for several days
after being exposed to a stressor, and also can show pronounced and prolonged post-stress depression
of home-cage activity; moreover, critical for modeling BD, HYPER rats assessed for 2-4 months
show “cycling” between manic-like outbursts and depression. (Note: prolonged depression occurs in
HYPER rats after a single acute stressor event and therefore represents the first rat model to meet the
DSM criterion for appropriate duration of depressive symptoms [persisting for more than 14 days]
following a discrete precipitating event). The HYPER rat also manifests other characteristics seen in
human BD – high levels of anxiety, a hyper-responsive pituitary-adrenal axis, elevated consumption
of alcohol, anhedonia (indicated by reduced propensity to consume highly palatable sucrose solutions),
cognitive differences from normal animals, abnormal midbrain dopaminergic transmission, and
skin lesions that point to genetic similarity to humans with BD. Finally, the behavioral abnormalities
of HYPER rats that mimic BD also respond to drugs used in the treatment of BD in humans; their
manic-like outburst of extreme hyperactivity when exposed to stress is blocked by treatment with
lithium or valproate. Lithium treatment also reduces “cycling” of HYPER rats that results in fewer
cycles and less severe cycling. The HYPER rat model shows the most extensive list of similarities to
human BD reported to date. Insofar as this model was not produced experimentally but instead arose
as a natural genetic variant, thereby reproducing human BD in this important respect, this would
seem to add considerably to its attraction as a model of BD. The promise of the HYPER rat is that it
embodies critical aspects of human BD in a rodent.
A Summary Table listing all phenomena observed in the HYPER rat relevant to human BD can be
found near the conclusion of this article.
In view of the behavioral similarities shown by the HYPER rat to critical behavioral characteristics
of BD in humans, the HYPER rat would seem extremely useful as a means to test/screen potential
new treatments for BD. Additionally, apparent similarities of pathophysiology and indications of similar
genetics of the HYPER rat to human BD supports its study to look for underlying causes of BD, and
also its use in genetic investigations where it can be employed using some of the latest techniques,
such as transcriptomics and RNA-Seq analysis, that are presently not possible in humans.